2&#39;,2&#39;-difluoro-2&#39;,3&#39;-dihydrofuran derivatives of the androstane and 19-norandrostane series



United States Patent Oflice 3,415,820 Patented Dec. 10, 1968 This invention relates to novel cyclopentanophenanthrene derivatives.

More particularly, the present invention relates to novel 2,2-difluoro-2,3-dihydrofuran derivatives of the androstane and l9-nor-androstane series.

The compounds of the present invention are of the formulas R1 1... H330 R j a l J and R2 HPHC 3 CFr I wherein R represents hydrogen, lower alkyl, lower alkenyl or lower alkenyl, R represents hydrogen, a carboxylic acyl group of less than 12 carbon atoms, tetrahydrofuran- 2-yl, or tetrahydropyran-Z-yl, R represents hydrogen or methyl, R represents lower alkoxy or a carboxylic acyloxy group of less than 12 carbon atoms, and R represents hydrogen, lower alkoxy or a carboxylic acyloxy group of less than 12 carbon atoms.

The expressions lower alkyl, lower alkenyl and lower alkenyl include aliphatic hydrocarbons of up to four carbon atoms such as methyl, ethyl, vinyl, ethenyl, propyl, butyl, propynyl, and the like. The expression lower alkoxy includes methoxy, ethoxy, and the like containing up to four carbon atoms.

The carboxylic acyl and acyloxy groups of the compounds of the present invention contain less than 12 carbon atoms and may be of a straight, branched, cyclic or cyclic-aliphatic chain structure. This structure may be sarurated, unsaturated, or aromatic and optionally substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like. Typical esters thus include acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, ,3 -chl0ropropionate, adamantoate, and the like.

The compounds of the present invention of Formula A above are prepared from a 2-lower alkoxymethyleneor 2-acyloXy-methylene-androstane or 19-norandrostane as illustrated below.

0R R Hm CF: (A)

In the above formulas, R, R R and R are as defined hereinabove. In practicing the above illustrated process, the starting material I, a 2-lower alkoXyrnethylene-3-oxo- 5a-androstane, 2 acyloXymethylene-3-0Xo-5a-androstane, or the corresponding l9-norandrostanes is reacted with an alkali metal salt of chlorodifiuoroacetic acid, e.g. sodium chlorodifluoroacetate in an inert solvent such as dimethyl diethylene glycol ether, dimethyl dipropylene glycol ether, and the likeat a temperature of from about C. to about C. to furnish the novel steroid (A). The reaction can be followed by UV. spectra and generally takes from about 1 to 12 hours or more. The amount of alkali chlorodifluoroacetate employed in the reaction can range from about 10 to 50, or more, molar equivalents, preferably from about 10 to 40. The starting material I can be obtained according to the procedure described in, for example, U.S. Patents 2,908,693, 3,135,743 and 3,145,200. To obtain the 17fi-tetrahydrofuran-2-yl ether and 17 6- tetrahydropyran-Z-yl ether derivatives, etherification of the corresponding 17/3-free alcohol can be accomplished either before or after preparation of the compounds of the present invention. The tetrahydrofuranyl and tetrahydropyranyl ethers can be prepared, e.g., by reaction of the 17/i-free alcohol with dihydropyran or dihydrofuran in the presence of an acid catalyst such as p-tolunesulfonic acid, p-toluenesulfonyl chloride, and the like. Similarly, esterification at C-17 can be accomplished either before or after preparation of the compounds of the pres ent invention by reaction of the 17/i-hydroxy compound with, e.g., a carboxylic acid anhydride in pyridine, or the like.

The compounds of the present invention according to Formula B above are prepared from a 2methylene-A 3-oxoor 2-substituted methylene-A 8-oxo-androstane or 19-norandrostane as illustrated below.

In the above formulas, R, R R and R are as defined above. The conversion of the starting material II into the novel compounds of Formula B is accomplished by treatment with an alkali metal salt of chlorodifiuoroacetic acid, e.g., sodium chlorodifluoroacetate in an inert solvent in the same manner as described above in connection with the novel compounds of Formula A. The starting material II can be obtained according to the procedure described in, for example, U.S. Patents 2,908,693, 3,145,- 200, 3,152,153 and 3,135,743. Etherification or esterification at C-l7 can be accomplished either before or after preparation of the compounds of Formula B.

The compounds of the present invention have a useful high anabolic-androgenic ratio and are especially valuable for treatment of those conditions or ailments where an anabolic effect together with a lower androgenic effect is desired such as in geriatrics, tissue build up, and like conditions. The compounds of the present invention or mixtures are administered in conjunction with one or more pharmaceutically acceptable excipients, orally or parenterally at a dosage level of from about 0.5 g. to mg. per kilogram of body weight per day. Higher or lower doses are also practical, depending on the degree and severity of the condition being treated. For making up a dosage, there can be employed pharmaceutically acceptable excipients such as gelatine, lactose, starches, talc, magnesium stearate, water, polyalkylene glycols, vegetable oils, gums, dextrine, and other known pharmaceutically acceptable carriers. They can also contain auxiliary substances, such as preserving, stabilizing, flavoring, wetting, emulsifying agents, buffers, and the like.

The following detailed examples serve to illustrate but are not intended to limit the scope of the present invention.

EXAMPLE 1 To a gently refluxing and stirred solution of 1 g. of 2- methoxymethylene-17fl-5a-androstan-3-one in 8 ml. of dimethyl diethylene glycol ether is added over a two hour period in a dropwise fashion, a solution of 12 molar equivalents of sodium chlorodifluoroacetate in 20 ml. of dimethyl diethylene glycol ether. The mixture is refluxed until the reaction is substantially complete, as determined by observation of the UV. spectra, and then filtered. The filtrate is evaporated in vacuo and the residue obtained is taken up in methylene chloride: hexane (1: and poured onto a 150 g. silica chromatographic column. The chromatographic column is then eluted with hexane containing increasing amounts of methylene chloride. The elu-ate 4 fractions are freed of solvent and those fractions eluted with and 100% methylene chloride, shown by thin layer chromatography to be about pure, are subjected to recrystallization from acetone:hexane to furnish 5a androstan-l7fi-ol-[2,3-d]-2', 2-difiuoro-3a-methoxy- 2, 3'-dihydrofuran and 5a-androstan-17fi-ol-[2,3-d1-2', 2-difluoro-3 ,B-methoxy-2, 3 '-dihydrofuran.

In the same manner, substituting 2-methoxymethylene-17/3-hydroxy-5a-androstan- 3 -one-17-acetate, 2-acetoxymethylene-17B-hydroxy-5a-androstan- 3 -one-17-acetate, Z-methoxymethylene-l 7 8-hydroxy- 1 7oc-ethynyl-5uandrostan-3 -onel7-acetate, 2-methoxymethylene-17,8-hydroxy-17a-ethyny1- androst-4-en-3 -one, 2-methylene-17a-ethynyl-17f?- (tetrahydropyran- 2-yloxy) -androst-4-en-3-one, 2-methoxymethylene-17fi-hydroxy-19-nor-5aandrostan-3-0ne, Z-methoxymethylene- 17 u-ethynyl- 17 ,B-hydroxy- 1 9-nor- 5u-androstan-3 -one, Z-methoxymethylene-17fi-hydroxy-17a-methyl-19- nor5a-androstan-3-one, Z-methoxymethylene-l7a-ethynyl-17/9-hydroxy- 19- norandrost-4-en-3 -one, 2-ethoxymethylenel7fl-hydroxy-5ot-androstan- 3 -one- 1 7-acetate, and Z-acetoxyrnethylene-17fl-hydr0xy-19-n0randrost-4- en-3 -one for 2-methoxyrnethylene-17fi-hydroxy-5a-androstan- 3-one, there is obtained the EXAMPLE 2 To a slurry of 1.0 g. of sodium hydride in 10 ml. of dry diethyleneglycol dimethyl ether under a dry nitrogen atmosphere is slowly added 1.0 g. of 5u-androstan-l7flol-[2,3-d]-2,2'-difiuoro 3 06 methoxy-Z,3-dihydrofuran in 10 ml. of dry diethyleneglycol dimethyl ether in a dropwise fashion over a 20 minute period. To this mixture is added dropwise, 0.9 g. of 2-chlorotetrahydrofuran over a 10 minute period.

The mixture is stirred at room temperature for an additional 30 minutes and then cautiously added to an ice water mixture with stirring. The organic phase is extracted with diehyl ether, dried and evaporated under reduced pressure to yield Sa-androstan-17B-(tetrahydrofuran2- furan which may be further purified via crystallization from acetonezhexane. 7

Similarly, by the use of 2-chlorotetrahydropyran in place of 2chlorotetrahydrofuran, there is obtained the corresponding 17,8-tetrahydropyran-2-yloxy derivative.

In the same manner, by substituting other 17,8-free alcohol compounds of the present invention or a mixture of the 3-isomers" which can later be separated, if desired, by chromatography and recrystallization, for Set-androstan-17B-ol- [2,3-d1-2, 2'-difluoro-3 'u-methoXy-Z, 3-dihydrofuran, the corresponding 17,8-ethers are obtained.

EXAMPLE 3 A mixture of 1 g. of a-androstan-17 8-ol-[2,3-d]-2',2- difluoro-3'a-methoxy-2,3'-dihydrofuran, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 5a-androstan- 17B-acetoxy [2,3-d] 2',2 difluoro-3'a-methoxy-2,3'- dihydrofuran which may be further purified through recrystallization from acetonezhexane.

By the use of other carboxylic acid anhydrides, e.g. propionic anhydride, valeric anhydride, caproic anhydride, and the like inplace of acetic anhydride, the corresponding l7 3-acylates are obtained.

In the same manner, by substituting 17,3-free alcohol compounds of the present invention or a mixture of the 3'-epimers of the compounds of the present invention which can be separated, if desired, after esterification by chromatography and recrystallization as described above, for 5a-androsjtan 17/3 ol [2,3-d] 2',2' diflUOI'O-3'amethoxy-2',3'-dihydrofuran, the corresponding 17,8-acylates, eg the acetates, are obtained.

EXAMPLE 4 Two milliliters of dihydropyran are added to a solution of 1 g. of 5a-androstan-17/3-o1-[2,3-d]-2',2-difluoro- 3'a-methoXy-Z,3'dihydrofuran in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then Washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 5a-androstan-l7fl- (tetrahydropyran-Z-yloxy) [2,3-d] 2',2' difluoro-3'amethoxy-2', '-dihydrofuran which is recrystallized from pentane.

EXAMPLE 5 To refluxing and stirred solution of 1 g. of 2-methoxymethylene-17fi-acetoXy-Sa-androstan-S-one in 8 ml. of dimethyl diethyleneglycol ether is added over a 1.5 hour period in a dropwise fashion, a solution of 20 molar equivalents of sodium chlorodifluoroacetate in 25 ml. of dimethyl diethyleneglycol ether. The mixture is refluxed under nitrogen until the reaction is substantially complete, as determined by observation of the UN. spectra, and then filtered. The filtrate is evaporated in vacuo to a residue containing a mixture of 5a-androstan-17fl-acetoxy-[2,3-d]2,2'-difiuoro-3'a-methoxy-2',3' dihydrofuran and Sa-androstan-l7fi-acetoxy-[2,3-d]-2',2'-difluoro-3' 3- methoxy-2,3-dihydrofuran which can be further purified by recrystallization from acetonezhexane to be employed as a mixture of isomers or separated by chromatography and recrystallization as described in Example 1.

What is claimed is:

1. A compound selected from the group consisting of:

and

wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl, R is selected from the group consisting of hydrogen, a carboxylic acyl group of less than 12 carbon atoms, tetrahydrofuran-2-yl and tetrahydropyran-Z-yl, R is selected from the group consisting of hydrogen and methyl, R is selected from the group consisting of lower alkoxy and a carboxylic acyloxy group of less than 12 carbon atoms, and R is selected from the group consisting of hydrogen, lower alkoxy and a carboxylic acyloxy group of less than 12 carbon atoms.

2. A compound according to claim 1 of the formula wherein R, R R and R are as defined therein.

3. A compound according to claim 2 wherein R and R are each hydrogen and R is methoxy.

4. A compound according to.claim 2 wherein R and R are each hydrogen and R is acetoxy.

5. A compound according to claim 2 wherein R is hydrogen, R and R are each methyl and R is methoxy.

6. A compound according to claim 2 wherein R is methyl, R and R are each hydrogen and R is methoxy.

7. A compound according to claim 2 wherein R is ethynyl, R1 is hydrogen, R is methyl and R is methoxy.

8. A compound according to claim 2 wherein R is ethynyl, R1 is hydrogen, R is hydrogen and R is methoxy.

9. A compound according to claim 2 wherein R is ethynyl and R is lower alkoxy.

10. A compound according to claim 2 wherein R is lower alkyl and R is lower alkoxy.

11. A compound according to claim 2. wherein R is acetoxy.

12. A compound according to claim 1 of the formula 23. A compound according to claim 12 wherein R is lower alkoxy.

17. A compound according to claim 12 wherein R is ethynyl, R is hydrogen, R is methyl and R is methoxy.

18. A compound according to claim 12 wherein R is methyl, R is hydrogen, R is methyl and R is methoxy.

19. A compound according to claim 12 wherein R is ethyl, R is hydrogen, R is methyl and R is methoxy.

20. A compound according to claim 12 wherein R and R are each hydrogen, R is methyl and R is methyl and R is methoxy.

21. A compound according to claim 12 wherein R is hydrogen.

22. A compound according to claim 12 wherein R is acetoxy.

References Cited UNITED STATES PATENTS 2/1963 Knox 260239.55 9/1964 Orr 260-239.55 4/1968 Fried 260239.55

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,415 820 December 10 1968 John H. Fried It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, lines 50 and 58, "alkenyl", each occurrence, shoul read alkynyl line 59, "ethenyl" should read ethynyl Column 3, line 64, after 17B- insert hydroxy Column 5, lines 65 to 75 and column 6, lines 25 to 35 the formula, each occurrence should appear as shown below:

2 cHR R 0P o i l H Column 6 lines 1 to 15 the formula should appear as shown below:

2 CHR R Cplumn 6 lines 45 and 47 "Rl", each occurrence should read R Column 7 line 8 cancel "and R is methyl" Signed and sealed this 1 th day of March 1970 (SEAL) Attest:

EDWARD M.PLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: 